SUMMARY OF WORK: Our laboratory uses multiple approaches to investigate potential predictors of coronary heart disease in apparently healthy subjects. A. The rate at which heart rate (HR) declines after cessation of maximal treadmill exercise has been proposed as an independent predictor of future coronary events (CE) both in symptomatic and asymptomatic populations. To examine this hypothesis in apparently healthy subjects, we determined the relationship between the decline in HR between peak exercise and 2 minutes post-exercise (HR recovery-2') in over 1000 Baltimore Longitudinal Study of Aging (BLSA) volunteers and subsequent development of CE (angina pectoris, myocardial infarction or coronary death). In a model containing standard coronary risk factors, treadmill aerobic capacity and ST segment response to exercise, age, gender, serum cholesterol level, aerobic capacity and ST-segment response, but not HR recovery-2' were independent predictors of CE. These findings cast doubt on the value of HR recovery as a coronary risk factor in subjects without apparent heart disease. B. To determine whether the apoliprotein E4 allele (apo E4) is associated with an increased risk of coronary events (CE) i.e. angina pectoris, myocardial infarction or sudden death, we determined apoE genotype in 731 asymptomatic Baltimore Longitudinal Study of Aging (BLSA) volunteers followed for a mean period of 17 years. Although the 200 subjects with at least one apo E4 allele and the 531 without apo E4 had similar levels of conventional coronary risk factors, CE developed in 21% of apo E4 subjects vs. 13% in the other group. On multivariate Cox analysis, the apo E4 allele was a strong independent predictor of events in men(RR=2.9,p<0.0001), but not in women (RR=0.9,p=ns). C. We examined the relative contributions of leisure time physical activity (LTPA) and aerobic fitness (peak VO2) during treadmill exercise to development of CE in 689 clinically healthy men 18-93 years old. Over a mean follow-up of 13.4 yrs, a CE occurred in 63 (9%). In multivariate Cox model, higher peak VO2 was protective against CE, both in men <65 years [RR=0.53/SD] and those >65 years [RR=0.61/SD]. In contrast, high intensity LTPA (greater than or equal to 6METs)had an independent protective effect in older but not younger men. Thus, strategies to increase LTPA may be more effective in reducing the CE incidence in older than younger men.